Fatal Insomnia

Fatal insomnia is a rare sleep disorder and a prion disease that interferes with sleep and leads to deterioration of mental function and loss of coordination leading to death occurs within a few months to a few years.

What causes fatal familial insomnia?

What areas of the brain are affected by the fatal familial insomnia?

The thalamus is the part of the brain that controls the sleep-wake cycle, but is also known as the “relay center” of the brain because it helps the different parts of the brain communicate with each other.

How does fatal familial insomnia progress?

Like all prion diseases, FFI is a progressive neurodegenerative disease, which means over time there are fewer neurons (nerve cells).

What is the mechanism by which FFI leads to neuronal loss?

Loss of neurons in the thalamus, as well as other mechanisms not yet fully understood, cause the symptoms of FFI.

How does FFI present clinically?

The first symptoms of FFI usually begin in mid-life and may include progressive insomnia, weight loss, lack of appetite, too high or too low body temperature, and rapidly progressive dementia. Almost all cases of FFI are caused by certain changes (mutations) in the PRNP gene and are inherited in an autosomal dominant manner.

What is the treatment for FFI?

There is currently no effective treatment for FFI, but research for a treatment and cure is ongoing. Death usually occurs within 12-18 months of the first symptoms.

What ages does FFI affect?

The first symptoms of fatal familial insomnia (FFI) usually begin between the ages of 32 and 62 (mean average 51 years), but have been reported to begin as early as 18 to as late as 72. It is important to note that insomnia is not always the first symptom of FFI; sometimes the first symptom is progressive dementia. When insomnia begins, it usually comes on suddenly and steadily worsens over a period of a few months.

What other symptoms are associated with FFI?

Other symptoms may include panic attacks, phobias, weight loss, lack of appetite, and having a body temperature which is too low or too high (hypothermia; hyperthermia). Autonomic disorders such as high blood pressure, episodes of hyperventilation, excessive sweating and salivation, and/or erectile dysfunction may occur.

How does fatal familial insomnia progress?

As the disease progresses, most people with FFI develop abnormal, uncoordinated movements (ataxia), hallucinations, severe confusion (delerium), and muscle twitches and jerks (myoclonus). Although the dementia may begin as forgetfulness and confusion, it leads eventually to the inability to walk and talk. Total inability to sleep is common towards the end of the course of the disease.

What are prion diseases and how does it relate to FFI?

Fatal familial insomnia (FFI) is a very rare form of genetic prion disease. In almost every case it is caused by a very specific mutation in the PRNP gene. This mutation causes the prion protein (PrP) that is made from this gene to be a different shape (fold incorrectly). Since the protein has a different shape, it cannot work correctly.

How does the prion lead to memory loss?

The abnormally shaped PrP (prion protein) causes changes in the thalamus including the progressive loss of neurons (nerve cells). The thalamus relays messages between different parts of the brain. It manages our sleep/wake cycle; the flow of visual, auditory, and motor information; our sense of balance; how we experience pain; aspects of learning, memory, speech and understanding language; and even emotional experiences, expression, and our personalities. Losing neurons in the thalamus causes many of the symptoms of FFI because the thalamus can no longer do all of its jobs well.

Can fatal insomnia affect other areas of the brain other than thalamus?

Although the main target of FFI is the thalamus, other parts of the brain are affected as well including the inferior olives. The inferior olives are part of the medulla oblongata and are important for coordinating our movements (motor control). Losing neurons in the inferior olives can make it harder for a person to control their movements as seen in later stages of FFI. Medical researchers are still working to understand how the abnormally folded PrP causes the progressive changes in the thalamus and other affected brain areas.

What causes the sporadic form of fatal insomnia?

In very rare cases of FFI, the cause is sporadic, meaning there is not a change in the PRNP gene. As of 2016, there have only been 24 reported cases of sporadic FFI. Sporadic FFI occurs when some of a person’s normal PrP (prion protein) spontaneously changes into the abnormal shape which causes FFI, and then somehow changes the shape of PrP in other neurons in a chain reaction.

How is FFI transmitted?

In most cases, a person with fatal familial insomnia (FFI) has inherited the genetic change from a parent with FFI. In order to have FFI, a person only needs one copy of their PRNP gene to carry the specific genetic change (mutation) that causes FFI. In other words, a person only needs to inherit the genetic change from one parent. In genetic terms, this is called autosomal dominant inheritance. In rare cases, FFI may result from a new (de novo) change in the PRNP gene, however it is not known how often a new mutation is the cause of FFI. New mutations can happen during the making of the egg or the sperm.

What is the chance of a person with fatal familial insomnia to transmit the disease?

A person that has the genetic change that causes FFI has a 50% chance with each pregnancy of passing along the changed gene to his or her child.

Can sporadic cases of fatal insomnia be transmitted?

In the rare sporadic cases of FFI, the disease is not inherited from either parent and cannot be passed down to their children.

How is fatal familial insomnia diagnosed?

The diagnosis of fatal familial insomnia (FFI) is first suggested by rapidly progressive cognitive impairment (dementia) along with behavior or mood changes, ataxia and sleep disturbances. Further diagnosis will include a sleep study and possibly a PET scan to confirm thalamic hypometabolism (meaning the thalamus in the brain is less active than it should be). The recommended PET scan is the fluorodeoxyglucose positron emission tomography (FDG-PET).

Can genetic tests be done to confirm the diagnosis of familial insomnia?

Genetic testing can confirm the diagnosis, but in the United States is only available if the person meets one of the following three criteria:

Diagnosis of FFI (usually through a combination of sleep study results and PET scan results)

Carrier testing for at-risk relatives and prenatal testing are possible for families with a confirmed diagnosis of FFI.

Is there any cure for fatal familial insomnia?

There is currently no cure for fatal familial insomnia (FFI) or treatment that can slow the disease progression. The management goal is to ease symptoms and keep the person with FFI as comfortable as possible.

What research is being done to evaluate potential treatments for fatal insomnia?

Current research is testing pentosan polysulfate, quinacrine (mepacrine), and amphotericin B and doxyclycline. Several forms of immunotherapy have reported success. The three main research areas focus on antibody vaccines, dendritic cell vaccines, and adoptive transfer of physiological prion protein-specific CD4+ T-lymphocytes. More research is being done to study how well these treatments work (effectiveness) and if the treatments are safe, but medical researchers believe that these or similar immunotherapies may offer hope for those with FFI in the future.

What is the prognosis for fatal familial insomnia?

After symptoms of fatal familial insomnia begin, the disease usually causes death within 12 to 18 months, with a range of a few months to several years. Researchers are working on finding a cure for this disease.

Prab R. Tumpati, MD.
Dr. Tumpati is the founder and medical director of W8MD Weight Loss, Sleep and MedSpa Centers. Dr Tumpati is board certified physician practicing sleep medicine, obesity medicine, aesthetic medicine and internal medicine. Dr. Tumpati’s passion is to educate patients and get to the root of the problem rather than "band aid medicine".
As a physician with fellowship training in Obesity Medicine, Dr. Tumpati has a unique approach to wellness, weight loss, and medical aesthetics with a focus on prevention rather than cure.
Dr. Tumpati takes pride in helping patients come of many chronic life style medications such as blood pressure, cholesterol or diabetes medications by helping them lose weight and change their life style.
Dr Tumpati believes in evidence based medicine rather than fad diets that do not work and works with each patient taking their unique situation in to consideration that causes them to gain weight so he can find a customized solution.
Serving as the medical director of the W8MD's New York City, Cherry Hill NJ and greater Philadelphia offices, Dr Tumpati is the leading weight loss, sleep and aesthetic medicine physician in the tristate areas of Pennsylvania, New Jersey and New York.